N -Halosuccinimide/AgNO3-efficient reagent systems for one-step synthesis of 2-haloglycals from glycals: Application in the synthesis of 2C-branched sugars via heck coupling reactions

Article abstract of DOI:10.1021/ol500039s

An expedient one-step synthesis of 2-iodoglycals and 2-bromoglycals from glycals using NIS/AgNO₃ and NBS/AgNO₃ as reagent systems has been developed. The utility of these 2-haloglycals has been demonstrated by converting them into 2C

Full text of DOI:10.1021/ol500039s

Letter
pubs.acs.org/OrgLett
N‑Halosuccinimide/AgNO3‑Efficient Reagent Systems for One-Step
Synthesis of 2‑Haloglycals from Glycals: Application in the Synthesis
of 2C-Branched Sugars via Heck Coupling Reactions
Suresh Dharuman and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
S
* Supporting Information
ABSTRACT: An expedient one-step synthesis of 2-iodoglycals and
2-bromoglycals from glycals using NIS/AgNO3 and NBS/AgNO3 as
reagent systems has been developed. The utility of these 2-
haloglycals has been demonstrated by converting them into 2C-
branched glycals via the Heck coupling reaction. Ferrier reaction of
tri-O-acetyl-2-iodoglycals followed by Heck coupling reaction with
methyl acrylate leads to 2C-branched O-glycosides.
arbohydrates play a crucial role in many biological
processes such as cell development, cell−cell and cell−
give the corresponding 2-iodoglycals.7b The other method
involves treatment of glycals with Br2 or SO2Cl2 to give the
corresponding dibromo or dichloro derivatives, which are
subjected to HBr or HCl elimination using DBU as a base to
give 2-bromo-9b and 2-chloroglycals,7c respectively.
We have been involved in the functionalization of glycals to
obtain important synthetic intermediates such as 2-nitroglycals,
2-deoxy-O-glycosides, 2-deoxy-1-glycopeptides, 1,2-diaminosu-
gars, 2-chloro-1-acetamido sugars, and 2-iodo-1-azido sug-
ars.11,6f In continuation of our efforts in this direction, we wish
to report an extremely simple one-step synthesis of 2-
haloglycals from glycals using N-halosuccinimides and a
catalytic amount of silver nitrate.
We recently reported the synthesis of 2-nitroglycals from
glycals using two different reagent systems.12 The first method
involves12a the use of an acetyl chloride−silver nitrate−
acetonitrile reagent system which affords the 2-nitroglycals or
2-nitro-1-acetamido glycosides depending on the experimental
conditions. The second one employs12b a combination of
tetrabutylammonium nitrate−trifluoroacetic anhydride−trie-
thylamine as a reagent system which gives 2-nitroglycals as
the sole products. In the course of developing new reagents for
the synthesis of 2-nitroglycals, we came across a literature
report about the use of a combination of N-bromosuccini-
mide−AgNO3 that acts as a nitrating agent for various
substituted aromatics.13 However, the nature of reactivity of
such a reagent combination is not clear, particularly how it acts
as a source of nitronium ion. If it is indeed a source of a
nitronium ion then we expect it to convert glycals to 2-
nitroglycals. On the other hand, it is well-known that N-
halosuccinimides (NXS; X = Cl, Br, I) are used as excellent
sources for the halogenations of olefins and aromatics. For
C
viral recognition, cell adhesion, inflammation, the immune
response, etc., and have become a central theme in
glycochemistry and glycobiology.1 Apart from the synthesis of
biological glycoconjugates, a wide range of synthetic carbohy-
drates are also being developed that may act as carbohydrate
mimetics. Among them, C-branched sugars are of much interest
as they are part of naturally occurring important antibiotics,
macrolides, and some polysaccharides.2 More recently, 2C-
branched sugars have also been identified as sugar mimetics of
N-acetyl sugars that are involved in the biosynthesis of lipids3
and as a result they have become important targets of synthetic
carbohydrate chemists. Thus, for example, Linker et al.4 made a
platform for the synthesis of 2C-branched sugars using a novel
ceric ammonium−nitrate mediated radical reaction on glycals.
Following this, more reports have appeared in the literature
involving the ring-opening reaction of 1,2-cyclopropanated
sugars,5 2-formyl glycals,6a,b and 2-nitrosugars.6c,f Besides these,
2-haloglycals have become a new entry to the 2C-functionalized
glycals and are widely used as important synthons in
carbohydrate chemistry.7 Thus, 2-iodo- and 2-bromoglycals
have been used in the synthesis of 2C-aryl glycosides,7e the
oxadecalin core of phomactin A,8 and biologically active
scaffolds such as chromans and isochromans.9 In these
syntheses, palladium-catalyzed domino, Sonogashira, and
Suzuki−Miyaura coupling reactions have been employed.
Apart from this, 2-chloroglycals are used in the synthesis of
benzannulated sugars via organolithium intermediates using t-
BuLi as a base.10 However, 2-bromo- and 2-iodoglycals are
more reactive and hence more often utilized. In spite of their
importance, there is no convenient method reported for their
synthesis. One of the known methods involves two steps in
which glycals are first treated with a source of iodonium ion in
aqueous medium to provide the corresponding 2-deoxy-2-
iodopyranoses, which are then eliminated with Ph2SO/Tf2O to
Received: January 7, 2014
Published: February 5, 2014
© 2014 American Chemical Society
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Letter
example, Olah et al. reported14 the halogenation of deactivated
aromatic systems with N-halosuccinimides along with BF3−
H2O as a Lewis acid catalyst. Keeping these observations in
mind, we were interested in finding out how the reagent
combination (NXS/AgNO3) behaves with glycals and expected
them to give 2-nitroglycals in line with the nitration of
aromatics (vide supra).
Table 1. Syntheses of 2-Iodoglycals and 2-Bromoglycals
from Various Protected Glycals
a
First, we performed the reaction of tri-O-benzyl-D-glucal 1
with N-iodosuccinimide (NIS)/AgNO3 in acetonitrile. To our
surprise, we isolated tri-O-benzyl-2-iodoglucal 2a (Scheme 1)
Scheme 1. Reaction of Tri-O-benzyl-D-glucal with NXS/
AgNO3 (or Lewis Acids)
as the sole product. Initially, we had used 1 equiv of AgNO3
and 1.2 equiv of NIS with respect to the glucal 1 and heated the
reaction mixture at 80 °C for 0.5 h, which gave 2a in 70% yield.
Since the product did not contain any elements of a nitro
group, we carried out the reaction of 1 with NIS in the presence
of a catalytic amount of AgNO3 (20 mol %, an optimized
amount), which gave 2a in 72% yield. We also studied the
reaction with various Lewis acids such as BF3·OEt2, AgOTf,
InCl3, Yb(OTf)3, and In(OTf)3. However, we did not observe
the formation of the expected 2-iodoglucal product 2a. Instead,
the isolated product was 2-iodo-1-succinimidyl glucoside 3
(Scheme 1), which is reported15 to be formed without the
addition of a Lewis acid also. In order to confirm if the
formation of 2 proceeds via 3, we treated it with AgNO3 at 80
°C in acetonitrile, but the starting material was found
unchanged even after 24 h. This implies that the reaction
does not proceed via the addition product 3.
a
Reaction conditions: glycals (0.24 mmol), NXS (0.28 mmol), AgNO3
b
(0.048 mmol), CH3CN (2.0 mL), N2 atmosphere, 80 °C, Isolated
yields after purification by silica gel column chromatography.
Next, we screened the reactivity of other nitrates such as
KNO3, NaNO3, and n-Bu4NO3, in place of AgNO3, wherein the
reactions took longer time and yields of 2 were very poor.
Hence, we explored the reactivity of various protected glycals
with N-halosuccinimides in the presence of a catalytic amount
of AgNO3. Thus, tri-O-benzyl-D-galactal 4 on treatment with
NIS/AgNO3 smoothly gave the corresponding 2-iodogalactal
4a in 68% in 30 min. Acetyl-protected glycals 5 and 6 also
underwent reactions to give the corresponding 2-iodoglycals 5a
and 6a in very good yields (Table 1, column 3). These
reactions were repeated on a 1 g scale, and comparable yields
were obtained. Silyl-protected glucal 7 and methyl-protected
glucal 8 were also treated with this reagent system to form the
corresponding products 7a and 8a, respectively. Further,
pentose sugars 3,4-di-O-acetyl-D-arabinal 9 and 3,4-di-O-
acetyl-D-xylal 10 and furanose glycal 11 also gave the 2-iodo
glycals 9a, 10a, and 11a, respectively. Likewise, all of the
protected glycals were treated with the N-bromosuccinimide/
AgNO3 reagent system, and the corresponding 2-bromoglycals
2b−11b were formed in moderate to good yields (Table 1,
column 4).
However, the corresponding 2-chloroglucal product 2c was
isolated only in 20% yield, and the remaining starting material
was recovered (Scheme 1). This might be because NCS is less
reactive than NIS and NBS.
A plausible mechanism for the formation of 2-haloglycals is
depicted in Scheme 2. N-Halosuccinimide acts as an electro-
philic source in the presence of AgNO3 and reacts with the
double bond of a glycal to give the oxonium ion intermediate C
along with the formation of silver succinimide D. The expunged
nitrate ion then reacts with C to give another intermediate E
which, under heating conditions, picks up a proton from C-2 in
an intramolecular fashion to yield 2-haloglycals F and nitric
acid. The silver succinimide D then reacts with the released
HNO3 to form succinimide and regenerates AgNO3 for the
1
catalytic cycle to resume. The H NMR spectrum of the crude
reaction mixture in the reaction of 6 with NIS/AgNO3 clearly
showed the presence of succinimide peaks at δ 2.6 and 8.7 in
CDCl3, confirming its formation as one of the products of the
reaction. Interestingly, we isolated small amounts of AgI (and
AgBr) in these reactions, which may act as a driving force for
the reaction since other Lewis acids do not lead to the desired
products.16
We then explored the reactivity of N-chlorosuccinimide
(NCS)/AgNO3 reagent system with tri-O-benzyl-D-glucal 1.
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In a similar way, tri-O-benzyl-2-iodogalactal 4a underwent
Heck coupling with different acceptors to give the coupled
products 15−17 in good yield. The reactions of tri-O-acetyl-2-
iodoglycals 5a and 6a were also carried out with methyl
acrylate, using Et3N as a base, which gave the corresponding
vinylic esters 20 and 23. Then, we chose allylic alcohol as an
acceptor for the Heck coupling reaction to access 2C-
substituted glycals, and as per our expectation, the products
18 and 19 were formed in reasonable yield, as summarized in
Scheme 3. Interestingly, the reaction of o-bromostyrene with 2a
gave two types of coupled products viz. dienes 21 and 22 in 3:1
ratio.
Scheme 2. Proposed Mechanism for the Formation of 2-
Haloglycals
We next explored the utility of tri-O-acetyl-2-iodoglycals to
obtain the corresponding 2,3-unsaturated O-glycosides using
the Ferrier reaction. Thus, in reaction of 5a with methanol and
allyl alcohol in the presence of BF3·OEt2, the reaction
proceeded smoothly to furnish the corresponding Ferrier
products 24 (anomeric ratio 5:1) and 25 in excellent yield.
Compound 5a underwent the Ferrier reaction with a
monosaccharide donor HOX to form the corresponding
disaccharide 26 (Scheme 4). Likewise, the tri-O-acetyl-2-
iodogalactal 6a underwent the Ferrier reaction to furnish the
O-glycosylated products 27−29 in moderate to good yields
(Scheme 4).
The palladium-catalyzed coupling reactions of vinyl halides
with activated and nonactivated alkenes as well as aromatics are
well recognized methods for C−C bond formation. 2-
Bromoglycals have been extensively used in Pd-catalyzed
reactions to annulate a further ring system.9b,e 2-Bromoglycals
have also been utilized in Heck coupling reactions with simple
olefins as well as activated olefins.17 Having developed an
efficient method for the preparation of 2-iodoglycals and 2-
bromoglycals, we wished to explore the utility of 2-iodoglycals
in the synthesis of 2-C substituted sugars which are present in
numerous natural products.18 We first attempted the Heck
coupling reaction of tri-O-benzyl-2-iodoglucal 2a with methyl
acrylate using Pd(OAc)2/PPh3 and Et3N in acetonitrile, which
afforded the coupled product 12. However, the reaction was
slow and took 2 days for completion. A solvent change to DMF
helped the reaction to proceed faster, and it took only 3 h to
form 12 in 85% yield. Various combinations were used, and the
most suitable catalyst combination was found to be Pd(OAc)2/
PPh3, K2CO3 with DMF as a solvent.
Scheme 4. Ferrier Reaction of Tri-O-acetyl-2-iodoglycals 5a
and 6a
Tri-O-benzyl-2-iodoglucal 2a was also converted to the
corresponding Heck-coupled products 13 and 14 using
appropriate alkene acceptors (Scheme 3).
The 2,3-unsaturated sugars obtained from the Ferrier
reactions were converted to the corresponding 2C-substituted
O-glycosides using Heck coupling reactions. Thus, compound
24 upon treatment with methyl acrylate using Pd(OAc)2/PPh3
in DMF solvent, which smoothly gave the vinylic ester 30 in
very good yield (Scheme 5). Likewise, the Ferrier product 27
was converted to the corresponding vinyl ester 31. The O-allyl
glucoside 25 was subjected to intramolecular Heck coupling
reaction using Pd(OAc)2/PPh3 to give the bicyclic compound
Scheme 3. Heck Reaction of 2-Iodoglycals with Different
Alkenes
Scheme 5. Heck Reaction of Ferrier Products with Methyl
Acrylate
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followed by a Heck coupling reaction leading to 2C-branched
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
■
*Email: vankar@iitk.ac.in.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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2007, 9, 5171−5174. (b) Rawal, G. K.; Rani, S.; Madhusudanan, K. P.;
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We thank the Department of Science and Technology, New
Delhi, for financial help in the form of a J. C. Bose fellowship
[JCB/SR/S2/JCB-26/2010]. SD thanks the CSIR, New Delhi
for a senior research fellowship. We also thank the Council of
Scientific and Industrial Research, New Delhi, for financial
support [Grant No. 02(0124)/13/EMR-II)] to Y.D.V.
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